Lap-Chee Tsui Genetics

Found the gene that causes cystic fibrosis

"Knowing science can enrich your life. Basically, science is a foundation for genuine common sense."

The Story

Richard Rozmahel passes time by reading the bulletin board hanging above the wheezing printer attached to the DNA sequencer. There’s an advertisement from a company selling genetic research chemicals. They’re offering a free T-shirt sporting the words: Ultra Pure Human Being. At the bottom of the ad he reads, “Send six peel-off seals from any GIBCO BRL Enzymes and receive an I Make My Living Manipulating DNA briefcase free.”

Ain’t it the truth, thinks Rozmahel to himself as he pulls yet another variation of the same tedious experiment from the printer. He looks at the printout absently as he makes his way back to his desk in the corner of the crowded genetics lab. People and equipment take up every possible space. Shelves groan with bottles, dishes and jars. He passes a friend staring into a microscope. A big humming refrigerator juts out into the passageway. Another student wears gloves while she puts hundreds of precisely measured portions of various liquids into tiny test tubes.

Rozmahel stops suddenly, just before he gets to his desk. Something is unusual about this printout. There it is: a three-base-pair deletion — a type of genetic mutation in a sequence of DNA. DNA molecules are long chains of instructions for making proteins, which themselves are long chains of connected molecules called amino acids. Each DNA instruction comes in a three-piece unit called a three-base pair, and each one stands for a particular amino acid needed in the construction of a protein. To Rozmahel, this three-base-pair deletion is as if one bead had vanished from a precious necklace. A mutation such as this might cause something as simple as a change in eye colour or as complex as a deadly disease.

Instead of sitting down at his desk, Rozmahel rushes to show his supervisor, Dr. Tsui (pronounced “Choy”). It’s almost six o’clock and most people have left for the night, but Lap-Chee Tsui is still working.

Tsui’s office is small. When Rozmahel arrives, Tsui is hunched over the desk, poring over some other experimental results. The shelves are loaded with books. Piles of paper cover every horizontal surface. Rozmahel looks at the shabby green rug while he waits.

“What is it, Richard?” asks Tsui, with a smile.

“I’m pretty sure I’ve found a three-base-pair deletion. Look here.” He indicates the two DNA sequences, one from a healthy person’s genes and one from a person with cystic fibrosis (CF) — a fatal disease that kills about one out of every 2,000 Canadians, mostly children. Cystic fibrosis is the most common genetic disease among Caucasians. Kids who have cystic fibrosis are born with it. Half of them will die before they are 25 and few will make it past 30. It affects all the parts of the body that secrete mucus; places like the lungs, the stomach, the nose and mouth. The mucus of kids with cystic fibrosis is so thick that sometimes they cannot breathe.

Tsui looks at the printout and says, “This is very good, Richard. Now show me that it’s real.” Tsui doesn’t seem excited at all, but he knows this is a solid clue, a major hint that they have found what they are looking for: the gene for cystic fibrosis, the cause of that terrible disease. But he has had false hopes before, so he is not going to celebrate until they check this out carefully. Maybe the difference between the two gene sequences is just a normal variation between individuals. If you take any two healthy people and compare 1,000 DNA bases, you have a good chance of finding the same thing Rozmahel had just found. There are plenty of little variations between individuals.

But Tsui remembers that day — May 9, 1989 — as the day they discovered the gene for cystic fibrosis.

He and his team spent the next five months making sure that their discovery was real, doing tests over and over to see whether the results would be the same. They identified a “signature” pattern of DNA on either side of the base-pair deletion, and using that as a marker they compared 100 healthy people’s genes with the identical DNA sequence from 100 cystic fibrosis patients. By September 1989 they were sure they had the cystic fibrosis gene.

As A Young Scientist...

As a boy Tsui dreamed of being an architect, and he still draws all his own diagrams and slides. He did not take up genetics until after he obtained his doctorate. He was more interested in studying the nature of diseases.

After Tsui earned his bachelor’s and master’s degrees from the Chinese University of Hong Kong, he went to study at the University of Pittsburgh in the United States. Hong Kong in those days was still a British dependency and Tsui was familiar with Western ways as practised by the British, but learning to adapt to the American way of doing things was challenging. He says, “It’s like if you go to play basketball, but all your life you’ve only played soccer, it takes a while to learn not to kick the ball.”

The first job Tsui got after receiving his doctorate was in Tennessee, at Oak Ridge National Laboratory. After spending about a year there, he took a position in the Department of Genetics at the Hospital for Sick Children in Toronto, Ontario, where he worked for 20 years and made his great discoveries. In 2002 Tsui returned to Hong Kong, where he became vice-chancellor of the University of Hong Kong.

The Science

Molecular geneticists try to understand the structure and function of genes. Lap-Chee Tsui is particularly interested in the gene for cystic fibrosis and other genes on human chromosome number 7. Chromosomes are threadlike strands found in the nuclei of animal and plant cells that carry hereditary information about the organism in DNA molecules.

After Tsui found the CF gene in 1989, he had to figure out exactly what that gene did. Over the years, he and his team have discovered that the DNA sequence with the mutation was part of the instructions for making a special protein called CFTR (Cystic Fibrosis Transmembrane conductance Regulator), a part of the cell membrane in certain special epithelial (surface) cells that generate mucus. These special cells might line the airways of the nose and lungs or the stomach wall.

The CFTR protein regulates a channel through the cell wall for chloride ions, which, through a process called osmosis, adjusts the “wateriness” of fluids secreted by the cell. Proteins are made of long chains of amino acids. The CFTR protein has 1,480 amino acids. Kids with cystic fibrosis are missing one single amino acid in their CFTR. Because of this, their mucus ends up being too thick and all sorts of things become difficult for them. Thanks to Tsui’s research, scientists have a much better idea of how the disease works. We can now easily predict when a couple will produce a child with cystic fibrosis. With increased understanding, scientists may also be able to devise improved treatments for children born with the disease.

Why do one in 25 Caucasians carry the mutation for CF? Tsui thinks that people who carry it may also have linked beneficial mutations that might, for instance, give them more resistance to diarrhea-like diseases. It’s not uncommon in nature to find the “good” linked with the “bad.”

1. Human chromosome 7: The cystic fibrosis gene sits on the long arm of chromosome 7. One out of every 25 people in the Caucasian population carries the genetic mutation for CF in this gene. Chromosome 7 has 150 million base pairs or units of DNA.

2. The cystic fibrosis gene: Using microbiological techniques, Tsui first localized the CF gene product to a region of the chromosome. The region has 230,000 DNA base pairs that spell out a series of 1,480 amino acids that curl up to make the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein. The little triangle shows the location of the three-base-pair deletion mutation that Tsui and his team discovered.

3. Model of CFTR protein in cell membrane: A normal gene makes CFTR that regulates the passage of chloride ions and hence the secretion of mucus in epithelial (surface) cells lining the gut, lungs and so on. One missing amino acid at this spot causes the majority of cases of CF. The remainder are caused by more than 1,200 other kinds of mutations of the CFTR gene, each accounting for a small percentage of cases.

Mystery

The genes of a monkey and a human are almost identical, varying by only about 2 percent. How can such a small difference result in such different animals? Why do humans develop into humans and monkeys into monkeys? It has to do with the way an organism controls which genetic instructions are read from its DNA. This control system is called “the regulation of gene expression” and is still very poorly understood. Tsui likens the situation with monkeys and humans to two orchestras, each having exactly the same instruments and the same music to play: they can sound entirely different if they have different conductors. The greatest mystery to Tsui is identifying and characterizing the “conductor” in the human genetic system.

Career Advice

So You Want to Be a Geneticist

Lap-Chee Tsui encourages people to consider a career in the “life sciences.” In addition to the typical jobs of technician or university researcher and professor, new opportunities are emerging as biotech company managers, or even biotechnology investment bankers. “As genomic biology is the key discipline that underlies all research in life sciences and medicine, a biology graduate does not have to be limited to jobs in the bio field,” says Tsui. There are many non-university research institutes, as well as biotechnology and pharmaceutical companies. After high school, it takes from 11 to 15 years of training to reach the level of an independent research biologist like Tsui. His advice to aspiring geneticists: “Cultivate your curiosity, persistence and passion.”

Tsui normally works about 10 to 16 hours a day. “I feel great if I can manage to get experiments to give results more or less as predicted to support my original hyptheses,” he says. But he gets even more excited when his experiments give results that are totally unexpected. The most exciting part of his work is when he can interpret unexpected data and uncover something new.

A wide spectrum of jobs is available to individuals with genetics training. Plant and animal breeders, medical specialists, pharmaceutical workers and government regulators are just a few possibilities.

Distinguished Scientist Award, The Canadian Society of Clinical Investigators, 1992

Sarstedt Research Prize, 1993

XII Sanremo International Award for Genetic Research, 1993

J.P. Lecocq Prize, Academie des Sciences, Institut de France, 1994

Canadian Medical Association Medal of Honour, 1996

Fellow, World Innovation Foundation, 2000

Foreign Associate, U.S. National Academy of Sciences, 2004

Mentor

K. K. Mark, who taught him how to concentrate on a single thing, and be good at it.
Roger Hendricks, who taught him how to encourage independent thinking and not to tell students what to do.
Manuel Buchwald, who taught him how to be critical and look at the broad perspective.
Han Chang who taught him how to be flexible, adaptive, and to understand the Western (American) way of thinking.